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A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: Comparison with effects of contraction and other AMPK activators

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Lai, Yu-Chiang Kviklyte, Samanta Vertommen, Didier Lantier, Louise Foretz, Marc Rider, Mark H. [UCL]

AMPK(AMP-activated protein kinase) is an attractive therapeutic drug target for treating metabolic disorders. We studied the effects of an AMPK activator developed by Merck (ex229 from patent application WO2010036613), comparing chemical activation with contraction in intact incubated skeletal muscles. We also compared effects of ex229 with those of the Abbott A769662 compound and AICAR (5-amino-4- imidazolecarboxamide riboside). In rat epitrochlearis muscle, ex229 dose-dependently increased AMPK activity of α1-, α2-, β1- and β2-containing complexes with significant increases in AMPK activity seen at a concentration of 50 μM. At a concentration of 100 μM, AMPK activation was similar to that observed after contraction and importantly led to an ∼2- fold increase in glucose uptake. In AMPK α1-/α2- catalytic subunit double-knockout myotubes incubated with ex229, the increases in glucose uptake and ACC (acetyl-CoA carboxylase) phosphorylation seen in control cells were completely abolished, suggesting that the effects of the compound were AMPKdependent. Whenmuscle glycogen levelswere reduced by∼50% after starvation, ex229-induced AMPK activation and glucose uptake were amplified in a wortmannin-independent manner. In L6 myotubes incubated with ex229, fatty acid oxidation was increased. Furthermore, in mouse EDL (extensor digitorum longus) and soleus muscles, ex229 increased both AMPK activity and glucose uptake at least 2-fold. In summary, ex229 efficiently activated skeletal muscle AMPK and elicited metabolic effects in muscle appropriate for treating Type 2 diabetes by stimulating glucose uptake and increasing fatty acid oxidation. © 2014 Biochemical Society.

Document type Article de périodique (Journal article) – Article de recherche
Publication date 2014
Language Anglais
Journal information "Biochemical Journal" - Vol. 460, no. 3, p. 363-375 (2014)
Peer reviewed yes
Publisher Portland Press Ltd.
e-issn 1470-8728
issn 0264-6021
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
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Bibliographic reference Lai, Yu-Chiang ; Kviklyte, Samanta ; Vertommen, Didier ; Lantier, Louise ; Foretz, Marc ; et. al. A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: Comparison with effects of contraction and other AMPK activators. In: Biochemical Journal, Vol. 460, no. 3, p. 363-375 (2014)
Permanent URL http://hdl.handle.net/2078.1/159752